HPV and Cancer Revisited

A recent post on my blog discussed a report by one of my colleagues, Dr. Maura Gillison, on the rise of HPV as a cause of oral cancer. This report is continuing to make news and was highlighted in an article published earlier this week in The Baltimore Sun.

Why is this important? As I discussed previously, this finding raises the possibility that immunization of boys with the HPV vaccine might be helpful not only to break the cycle of sexually transmitted HPV causing cervical cancer, but also to protect the boys themselves from oral cancer.

But the study has implications beyond that. Until recently, the major risk factors for oral cancer were age, alcohol consumption, and smoking. That profile is changing, though, as HPV is becoming a more important cause of this disease.

More recently, doctors are seeing oral cancers arising in younger men with no history of smoking or heavy drinking. Oral cancers in this population are increasing in frequency, and if the trend continues, the number of oral cancer cases may surpass the number of cervical cancer cases in the US.

Fortunately, Dr. Gillison’s group found something else. The prognosis of patients with HPV-associated oral cancer is better than the prognosis of patients whose oral cancer is not caused by the virus.

I guess that’s a silver lining, but all in all it would be better not to get cancer at all!

Illustration courtesy of MedlinePlus

Related posts you may be interested in:
HPV, STIs, and Teenaged Girls: What does 1 in 4 mean and what can be done?
HPV Vaccination: It may not just be for girls
The Virus/Cancer Connection (Part 4): Vaccines, Cervical Cancer, and a Recap

HPV, STIs, and Teenaged Girls: What does 1 in 4 mean and what can be done?

Several of my recent blog postings have dealt with viruses that cause cancer. One cancer-causing virus that has been in the news lately is human papillomavirus (HPV), a sexually transmitted virus that can cause cervical cancer. The development of a vaccine that protects women from the specific HPV strains that cause cervical cancer was a major step forward in cancer prevention.

Although it is clear that the vaccine reduces infections with these HPV strains, because of the long time interval between infection and the development of cancer it has not yet been proven that vaccination will decrease the incidence of cervical cancer.

However, according to data presented recently at the annual meeting of the Society of Gynecologic Oncologists (SGO), there is already evidence that vaccination decreases the incidence of abnormal Pap smears and the number of procedures needed to evaluate these abnormal screening tests. This is tremendously important news. The cellular abnormalities detected by a Pap smear are clearly precursors of cervical cancer, so it is extremely likely that a decrease in abnormal Pap smears will directly lead to a decrease in cervical cancer.

This is what an abnormal Pap Smear looks like.
The red arrow points to a cancer cell.

But there are other important benefits from decreasing the frequency of abnormal Pap smears. In the words of Dr. Warner Huh, from the University of Alabama, Birmingham, “Very few of us can identify with cervical cancer, but almost every woman in the United States can identify with an abnormal Pap smear.” In fact, in the course of a lifetime, nearly 1 in 3 women will have an abnormal Pap smear and have to deal with both the procedures that are required to investigate the abnormality, and also with the anxiety of believing that she may have cancer. So, clearly, decreasing the rate of abnormal Pap smears would be a huge benefit to all women.

The benefits extend beyond avoiding anxiety and medical tests. There is a societal cost savings as well: According to the SGO, the combined costs of screening and treating cervical abnormalities in the US alone amounts to $4 billion per year. That’s quite an opportunity for cost reductions!

In related news, a report published this past week stated that as many as 1 in 4 teenaged girls in the US has a sexually transmitted infection. The medical blogosphere has been abuzz with this information and its implications.

At first blush, this is a horrifying statistic. After all, when most people think of sexually transmitted infections, they think of gonorrhea, Chlamydia, herpes or syphilis, and it would be awful to imagine that 25% of the teenaged girls in the US have one of these infections. However, HPV is included in the definition of sexually transmitted infections used by this report. As many as 80% of women in the US show evidence of having been infected with HPV at some point. Including HPV infections in the definition of sexually transmitted infections, then, will substantially distort the numbers. After all, by this definition, more than 80% of adult women in the US have an STI! Compared to that, 25% doesn’t seem as bad.

This number does, however, add to the importance of vaccinating girls against HPV. If girls are getting infected in their teenaged years, and if vaccination can prevent infection, abnormal Pap smears, future medical procedures, and hopefully the development of cancer, this suggests that vaccination should happen early (ages 8 or 9?), well before girls become sexually active, in order to maximize the benefits.

HPV Vaccination: It may not be just for girls

On January 29, I thought I was culminating a discussion of the virus/cancer connection by talking about the link between HPV and cervical cancer, and how the development of a vaccine for HPV could prevent cervical cancer in women.

Shortly after that entry posted, Maura Gillison (a colleague of mine), published an article in the Journal of Clinical Oncology on the growing importance of HPV as a cause of oral cancer. Why is that relevant? One reason is that this represents a shift in the importance of various causes of oral cancer, away from tobacco and towards a virus. This reflects the huge success we’ve had in diminishing tobacco use. As tobacco fades as the leading cause of oral cancer, virus-induced cancer is becoming more common. Interestingly, there is some speculation that this finding might also reflect changes in sexual behavior patterns, especially related to oral sex.

The finding that HPV is now a leading cause of oral cancer means that vaccination of men could significantly impact on the incidence of this disease. So a vaccine (that until now has been given almost exclusively to girls to prevent cervical cancer) could also be given to boys to prevent oral cancer in people of both genders.

The idea of giving the vaccine to boys is not new. This article, from last May, discusses heterosexual sex as the main mode of transmission of HPV to girls, and suggests that vaccinating boys could help break the cycle of sexually transmitted cervical cancer. At the time the article was written, it had recently been discovered that HPV can cause throat cancer, but at that point throat cancer was still more commonly caused by smoking and drinking, so the impact of HPV vaccination on throat cancer was expected to be small.

So what makes Maura’s article a more compelling argument to vaccinate boys is the fact that oral cancer is now more commonly caused by HPV than by tobacco, making the impact of the vaccine greater.

Merck, the manufacturer of Gardisil, the only HPV vaccine available in the US, has been conducting trials of vaccine in boys to determine how tolerable it is. As expected, the vaccine is well tolerated and effective. Effectiveness was measured by determining how many boys who received the vaccination developed antibodies against the virus (almost 100%). There was no difference in effectiveness, measured in this way, between boys and girls.

So… will vaccinating boys have any effect on cervical cancer, oral cancer, or anything else? No one really knows yet. It will be fascinating to watch as these trials are conducted.

The Virus/Cancer Connection (Part 4): Vaccines, Cervical Cancer, and a Recap

Everyone is familiar with the idea that getting vaccinated can keep viruses away. Every year millions of people get the flu shot for just that purpose. If viruses can cause cancer, can vaccines be used to prevent cancer? Of course they can! The best example of this is a pair of new vaccines called Gardasil and Cervarix which prevent cervical cancer.

Cervical cancer? The cancer women get Pap Smears to detect?

Yes, cervical cancer. It turns out that cervical cancer is caused by a virus called human papilloma virus, or HPV. There are more than 100 different strains of HPV, and at least 30 of them are transmitted through sexual intercourse. HPV infection is common, and by age 50 at least 80% of women will have acquired a genital HPV infection.

If 80% of women develop an HPV infection, why don’t 80% of women get cervical cancer? Most of these infections are cleared by the woman’s immune system with no long term consequences. Fortunately, only a small fraction of HPV strains are capable of causing cancer, and these only in the case of a persistent infection. So once again, it appears that a viral cause of cancer requires more than just exposure to the virus. For cancer to develop, it requires a complex interaction between the virus and the patient’s immune system.

Where do the vaccines fit in?

The vaccines cause the body to develop antibodies against 4 of the most common strains of HPV that are associated with persistent infection and with the development of genital warts and cervical cancer. These antibodies help the patient clear the viral infection before it becomes persistent, and thus prevent the development of cancer.

Why is this controversial?

Well, these vaccines are preventive, rather than therapeutic. So they have to be given before exposure to the virus. If the virus is spread through sexual intercourse, that means prior to the initiation of sexual activity. The Advisory Committee on Immunization Practices recommends the vaccine for girls as young as 11, and some school districts have begun to require HPV vaccination just as they require vaccination against chicken pox and whooping cough. One possibly troublesome issue about requiring an HPV vaccination is that some parents may have an issue with vaccinating their little girls against a sexually transmitted infection.

What about men?

Don’t sexually transmitted infections go both ways? Certainly they do. But because cervical cancer is a disease limited to women, all of the clinical testing was done on women, so the vaccines are currently only approved for women (and girls). Clinical trials are ongoing in men, but because they are not completed, there are no data regarding the safety or efficacy of the vaccine for men and no data about whether vaccinating men impacts the rate of cervical cancer in their partners. Also, HPV has been associated with penile and anal cancers in men, so there may be a direct benefit to vaccinating men, but this has not yet been studied either.

Recap: So what have we learned?

Although we don’t usually think about it this way, cancer can be caused by a viral infection. Many cancer-associated viruses, like EBV, are very common, and yet they rarely cause cancer. This is because the interaction between the virus and the patient is quite complex, and only in very rare circumstances does EBV (or HPV, for that matter) cause cancer. However, the fact that viruses can cause cancer teaches us a lot about the role of the immune system in controlling cancer, the impact of the environment on cancer risk, and a host of other lessons that are important in thinking about all forms of cancer.

Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 3): The Immune System Fights Cancer

In previous entries, I have discussed the connection between viruses and cancer, focusing on the roles viruses might play in the development of tumors, especially in patients with compromised immune systems. Today, I will discuss ways in which oncologists might exploit the virus/cancer connection to treat and prevent cancer.

First: Breaking News

Just to demonstrate that nothing in medicine is static for long, just this month another cancer was found to be associated with a virus. Interestingly, the discovery was made in the laboratory of the husband and wife team that identified HHV-8 as the cause of Kaposi’s sarcoma. Using a sophisticated DNA analysis technique, these scientists found that cells from a rare type of skin cancer called Merkel cell carcinoma (coincidentally, also a cancer found predominantly in the elderly) contain an embedded virus called polyoma virus. This adds Merkel cell carcinoma to the ever-expanding list of virus-associated human cancers, and increases the importance of understanding the complicated interactions between us and viruses.

polyoma virus through an electron microscope

Immune competence as cancer therapy

My discussion of viruses as a cause of cancer began with the identification of HHV-8 or KSHV as the cause of Kaposi’s sarcoma. I talked about how Kaposi’s sarcoma was an “AIDS-defining Illness” in the early days of the AIDS epidemic, and that it had virtually disappeared since the advent of highly active antiretroviral therapy (HAART), but was recently making a resurgence, at least in San Francisco. The observation that Kaposi’s sarcoma is an AIDS-defining illness that almost vanished when HIV infections became controlled with better combination treatments suggests a way to treat KS that I’ll talk about shortly.

But first… are there other virus-associated cancers that seem to depend on the patient’s immune status?

In fact, there are.

One of the most dreaded complications of organ transplantation (other than rejection) is the development of post-transplant lymphoproliferative disorder (PTLD). PTLD arises from an imbalance between lymphocytes infected with Epstein-Barr Virus (EBV) and those that keep them in check. As I discussed before, EBV is a very common virus. In the United States, estimates are that 90-95% of the adult population has had an EBV infection. Your body never rids itself of EBV. When the illness caused by the infection ends, the virus becomes dormant in white blood cells called B lymphocytes. EBV-infected B lymphocytes become immortal, and would grow without limit were it not for another type of white blood cell, called T lymphocytes, that keep the EBV-immortalized B lymphocytes under control.

Patients who have received an organ transplant must take immune suppressive drugs forever to keep from rejecting their transplant (although this may not be true… a topic for the next blog entry). When these drugs inhibit the T lymphocytes that control the EBV-infected B lymphocytes the B lymphocytes divide and grow, resulting in PTLD. PTLD can range from mild (just a swollen lymph node) to very aggressive, indistinguishable from Burkitt’s Lymphoma.

Lymph node biopsy

from a patient with

Burkitt's Lymphoma

Fortunately, the treatment for even the worst cases of PTLD begins with a very simple step – stopping the immune suppression. In many cases this is sufficient to restore the balance between the T and B lymphocytes and reverse the disease process. Ultimately, what doctors must do is find the right dose of immune suppression to prevent rejection while maintaining control over the EBV-infected lymphocytes.

Might this work for KS, too? Studies show that it might.

Patients who develop KS before they begin HAART, who are started on this treatment, have an 82.6% reduction in death from KS compared with patients who do not start HAART. In fact, HAART alone can lead to resolution of KS. Interestingly, it may be that a reduction in HIV viral load, rather than improvement in the function of the immune system, is what makes the KS go away. Regardless of why, restoring the immune system can make at least two types of virus-driven cancer (KS and PTLD) go away, with far fewer side effects than chemotherapy. Hopefully, we will continue to find ways to harness the immune system, based on this model, to fight off cancer.

Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 2): In the beginning, there were chickens

On December 15th, I began a discussion about the virus/cancer connection and the role of HHV-8 in causing Kaposi Sarcoma, especially in AIDS patients. Is Kaposi Sarcoma the only cancer caused by a virus? No. In fact, the observation that viruses can cause cancer dates back to the beginning of the 20th century.

In 1909 Peyton Rous discovered that a virus could cause sarcomas in chickens. For discovering the Rous Sarcoma Virus, Dr. Rous was awarded the Nobel Prize in 1966. This discovery led directly to the discovery of cellular oncogenes (genes that cause cancer) by Bishop and Varmus, which also was rewarded with a Nobel Prize.

Subsequently, numerous other human cancers have been associated with viral infections. The most important of these is Burkitt’s lymphoma. Burkitt’s lymphoma comes in three varieties: one form is endemic to sub-Saharan Africa and is most likely caused in large part by infection with a virus called Epstein-Barr Virus (EBV, which also causes mono), one form is sporadic (as opposed to endemic), and one form is associated with immunodeficiencies such as AIDS. The endemic form of Burkitt’s lymphoma typically causes a large, painful jaw mass, while the sporadic form more commonly involved the intestines. Interestingly, another name for EBV is Human Herpesvirus-4 (HHV-4). EBV, or HHV-4, also causes nasopharyngeal carcinoma in southeast Asia (and elsewhere). It is clear that there is a real connection between viruses and cancer.

EBV is a very common virus. According to the Centers for Disease Control, 90-95% of the US adult population has had an EBV infection. When contracted in early childhood, EBV causes the common cold. When contracted during adolescence, the same virus causes mononucleosis 35-50% of the time. While most people who get EBV will not develop cancer, some unfortunately do. Why? No one fully understands yet, but there is a lot of active research trying to better understand the relationship between viruses and cancer.

So maybe we’ll have to change the answer to the question I posed before: Is cancer a contagious disease? No, but contagious diseases might contribute to the development of some forms of cancer. This is why it is important to continue research on understanding and controlling infections.

How do viruses cause cancer? Well, EBV and HHV-8 are both thought to cause cancer by controlling the activity of genes already present in cells called proto-oncogenes. A few years ago, a group of scientists in Spain proposed another way viruses might cause cancer. These scientists were investigating Ewing’s sarcoma (one of my main research interests), the second most common bone cancer in adolescents and young adults.

This is an x-ray of the leg of a patient

with Ewing's sarcoma.

Almost all cases of Ewing’s sarcoma have a particular chromosomal abnormality in them, where a piece of either chromosome 11 or chromosome 21 is attached to chromosome 22. This so-called “translocation” results in the production of a new protein, not found anywhere else in the human body, which is thought to be the direct cause of the cancer.

This is a diagram of a translocation

between two chromosomes.

The Spanish scientists announced, in an article published in 1999, that a gene called E1A (from a kind of cold virus called adenovirus), when put into cervical cancer cells in the laboratory, caused the characteristic translocation between chromosomes 11 and 22 found in Ewing’s sarcoma. Other groups have not been able to repeat this finding, so it remains very controversial, and yet if true, this would suggest that there are numerous ways that viruses could cause cancer in people and would potentially dramatically increase the number of types of cancers that could be related to viruses.

Kaposi’s Sarcoma and the Virus/Cancer Connection (Part 1)

Is cancer a contagious disease? The simple answer to that question is “No.” At least, that’s what we tell people. You can’t catch cancer from someone who has it. If a cancer patient is isolated, it’s to protect the patient from us, not the other way around. But, as is often the case, the truth is not quite so simple.

Let’s take a trip back in time. It’s 1984. Arguments rage about what to call the newly discovered virus that seems to cause this new disease called Acquired Immune Deficiency Syndrome (the American group proposed calling the virus HTLV-III while their French competitors wanted to call it LAV). When the dust settles, the virus is called HIV, and it quickly becomes clear that infection with HIV is not the same thing as having AIDS. So how do we define AIDS? Well, a person has AIDS if s/he is infected with HIV and has one of the so-called “AIDS Defining Illnesses.” Interestingly, one of these is a kind of cancer called Kaposi’s Sarcoma. Kaposi's Sarcoma causes nodules or blotches that may be red, purple, brown, or black. They are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract and respiratory tract. Growth can range from very slow to explosively fast, and may be fatal.



All of the other AIDS defining illnesses, however, are infections that usually strike people with weakened immune systems (like cancer patients). So what is Kaposi’s Sarcoma doing on the list?

That question remained a mystery for quite a while. After all, although Kaposi’s Sarcoma was first described in 1872, it was originally known as a disease that affected older men from the Mediterranean region or who were of Ashkenazi Jewish descent. Yet, these men didn’t have AIDS, and no one knew why Kaposi’s sarcoma seemed to disproportionately affect this population. There is also a form of Kaposi’s Sarcoma endemic to sub-Saharan Africa, and although HIV infection is prevalent there now, that was not the case when endemic Kaposi’s Sarcoma was first described.

An answer to this mystery became apparent in 1994 when a group at Columbia University showed that Kaposi’s Sarcoma is actually caused by a virus. Originally they called it Kaposi’s Sarcoma Herpes Virus (because it is closely related to the viruses that cause herpes), but is has since been renamed HHV-8 (human herpesvirus 8). Subsequent work has shown that all forms of Kaposi’s Sarcoma are associated with an HHV-8 infection.

Over the years since the beginning of the AIDS epidemic, we have gotten pretty good at treating HIV infection, and with HAART (highly active anti-retroviral therapy), HIV infection has morphed from a rapidly fatal infection to a chronic disease. A by-product of the advent of HAART was the apparent disappearance of Kaposi’s Sarcoma. What was once an AIDS-defining illness, affecting as many as 80% of AIDS patients, there have been very few cases in the past 10 years.

Until now.

15 Kaposi’s Sarcoma cases were recently identified by doctors at San Francisco General Hospital. Surprisingly, these cases occurred in patients whose HIV infections were well controlled on HAART. This has prompted speculation about what happens as the immune system ages. These men all have undetectable HIV levels and normal numbers of white blood cells. Of course, so do the Ashkenazi Jewish men who used to be the primary group of KS patients. So what does this mean? Right now, no one is certain. But like all medical mysteries, we will all be a lot smarter once we figure it out.